The object of this research is to elucidate the role of glycosphingolipids in cerebral metabolism using brain tissue obtained at autopsy, fibroblasts cultured from skin biopsies and cell strains of neurological origin. By isolating all the stored complex carbohydrates from tissue in four specific hydrolase deficiencies (GM1-gangliosidosis, GM2-gangliosidosis Type II, fucosidosis and mannosidosis) we hope to understand the relative importance of glycosphingolipids, glycopeptides and oligosaccharides in the neuropathology of these diseases. By studying the iso enzymes of beta-galactosidase and gamma-fusosidase (both normal and mutant) using techniques such as electrophoresis, enzyme purification by affinity chromatography and localization of genes for these iso enzymes to specific chromosomes by screening man-mouse hybrid cells, we hope to better understand the fundamental biochemical defect and offer a rational basis for remedial therapy. By comparing the advantages (isotopic tracer studies, membrane changes, model for attempts at enzyme replacement therapy, etc.) and disadvantages (for example the lack of ability to synthesize brain gangliosides and absence of endoglycosidases found in liver) of cultured human skin fibroblasts, we hope to ascertain the validity of their use for the study of these inherited disorders. Finally, by studying glycosphingolipid metabolism in cell strains of neurologic origin (neuroblastoma, schwannoma and astrocytoma) treated either with inhibitors of specific lysosomal hydrolases, neurologic "messengers" (cyclic AMP, prostaglandins E1 and E2 and neurotransmitters) as reputed toxins (eg: psychosine), we hope to relate the ganglioside enrichment of neurons to the specific function and morphology of these cells.